What are the latest guidelines for managing schizophrenia?

Latest Guidelines for Schizophrenia Management

The most recent 2025 INTEGRATE international guidelines from The Lancet Psychiatry provide the current algorithmic approach to schizophrenia treatment, emphasizing antipsychotic monotherapy as first-line, comprehensive cardiometabolic monitoring, and specific strategies for managing residual symptoms. 1

Core Pharmacological Approach

First-Line Treatment Strategy

• Initiate antipsychotic monotherapy as the foundational treatment approach for schizophrenia, with selection based on side-effect profiles through shared decision-making. 1
• Antipsychotics effectively reduce positive symptoms but may have limited impact on negative symptoms and cognitive deficits. 1
• At least 20% of patients do not achieve substantial response from monotherapy, and 70% require long-term or lifetime medication without achieving complete recovery. 1

Treatment-Resistant Cases

• Trial clozapine after two adequate monotherapy trials with different antipsychotics have failed, ensuring no absolute contraindications exist. 1
• Before declaring treatment resistance, verify medication adherence using long-acting injectables or blood concentration measurements to confirm compliance and therapeutic serum levels. 1
• Target clozapine plasma levels of at least 350 ng/mL, with consideration for increasing to 350-550 ng/mL if inadequate response after 12 weeks. 2

Comprehensive Monitoring Protocol

Baseline Assessment (Before Starting Antipsychotics)

Obtain the following measures before initiating any antipsychotic: 1

• BMI and waist circumference
• Blood pressure
• HbA1c and fasting glucose (or random glucose if fasting unavailable, followed by fasting if abnormal)
• Lipid panel
• Prolactin level
• Liver function tests
• Urea, electrolytes, and renal function
• Complete blood count
• Electrocardiogram

Follow-Up Monitoring Schedule

• Check fasting glucose at 4 weeks after antipsychotic initiation. 1
• Monitor BMI, waist circumference, and blood pressure weekly for 6 weeks following initiation or switch. 1
• Repeat all baseline measures at 3 months, then annually thereafter. 1
• For clozapine specifically, follow specialized monitoring guidelines for hematological safety. 1

Managing Residual Symptoms

Negative Symptoms

When positive symptoms are controlled but negative symptoms persist: 1

• Rule out psychosocial factors that may exacerbate or maintain negative symptoms and encourage social engagement.
• Consider gradual dose reduction of antipsychotic while remaining within therapeutic range if positive symptoms are well controlled. 1
• Switch to cariprazine or aripiprazole as suitable options for predominant negative symptoms. 1
• Low-dose amisulpride (50 mg twice daily) can be considered when positive symptoms are not a concern. 1
• Antidepressant augmentation may provide modest benefit even without depression diagnosis, though monitor for pharmacokinetic/pharmacodynamic interactions including serotonin syndrome. 1
• Trial aripiprazole augmentation in patients not already on a D2 partial agonist, with clear explanation of risks and benefits. 1

Cognitive Symptoms

• Review and minimize anticholinergic burden of the medication regimen, noting that clozapine, olanzapine, and quetiapine have the highest central anticholinergic activity. 1
• Consider gradual antipsychotic dose reduction within therapeutic range if positive symptoms are controlled. 1
• Cognitive remediation strategies include switching to an antipsychotic with more benign metabolic profile, adjunctive metformin, or GLP-1 receptor agonist treatment. 1

Depressive Symptoms

• Address depressive symptoms with appropriate interventions when they emerge during treatment. 1

Cardiometabolic Management

Prevention Strategies

• Offer lifestyle advice (healthy diet, physical activity promotion, tobacco cessation) to all patients. 1
• Initiate adjunctive metformin when starting antipsychotics with poor cardiometabolic profiles (olanzapine and clozapine). 1
• Start metformin at 500 mg once daily, increase in 500 mg increments every 2 weeks up to 1 g twice daily based on tolerability, using modified-release preparation when available to minimize gastrointestinal side effects. 1
• Assess renal function before commencing metformin and avoid in renal failure. 1
• Monitor annually: liver function, HbA1c, renal function, and vitamin B12. 1

Managing Established Metabolic Issues

• Switch to antipsychotic with more benign metabolic profile when appropriate. 1
• Consider adjunctive GLP-1 receptor agonist for metabolic concerns. 1

Antipsychotic Polypharmacy Considerations

Current Guideline Stance

While most guidelines recommend against routine antipsychotic polypharmacy, there is evolving recognition of specific situations where it may be beneficial: 1

• American Psychiatric Association guidelines endorse monotherapy and do not acknowledge situations recommending polypharmacy. 1
• NICE guidelines (2014, reviewed 2019) allow adding an additional antipsychotic to augment clozapine if clozapine monotherapy proves ineffective, selecting drugs that don't compound clozapine's common side effects. 1
• World Federation of Societies of Biological Psychiatry recommends polypharmacy only in treatment-resistant cases, noting that combining clozapine with another second-generation antipsychotic (possibly risperidone) may have advantages. 1

Evidence-Based Polypharmacy Approach

• Combining aripiprazole with clozapine may effectively reduce treatment side effects or residual symptoms, and this likely applies to other partial dopamine-2 agonists with clozapine. 1
• Polypharmacy does not appear to increase mortality but may increase treatment-related side effects, though some combinations may reduce side effects. 1
• Polypharmacy is used in 10-20% of outpatients and up to 40% of inpatients in clinical practice, despite guideline recommendations. 1

Managing Specific Side Effects

Akathisia

• Manage with dose reduction as first approach. 1
• Switch to quetiapine or olanzapine as alternative. 1
• Adjunctive propranolol (10-30 mg, two to three times daily) may be used. 1

Hyperprolactinemia

• Counsel patients on risks of untreated asymptomatic hyperprolactinemia, including reduced bone mineral density and increased breast cancer risk in women. 1
• Switch to a D2 partial agonist when appropriate for symptomatic hyperprolactinemia. 1
• Alternatively, consider adjunctive low-dose aripiprazole. 1

Substance Use Comorbidities

• Provide information, education, and non-judgmental supportive approach. 1
• Co-work with specialist substance use disorder services. 1
• Offer varenicline, bupropion, or nicotine replacement therapy for tobacco cessation, as these have proven efficacy in schizophrenia patients. 1
• Offer naltrexone for reducing harmful alcohol use in schizophrenia patients. 1

Common Pitfalls to Avoid

• Do not declare treatment failure prematurely—ensure adequate dose (therapeutic range) and duration (at least 4 weeks at therapeutic dose) before switching. 1, 2
• Do not overlook non-adherence as a cause of apparent treatment resistance—verify compliance before escalating treatment. 1, 2
• Do not neglect cardiometabolic monitoring—antipsychotic-related metabolic complications significantly impact morbidity and mortality. 1
• Do not ignore physical health—address modifiable risk factors (exercise, diet, obesity, smoking) alongside mental health treatment. 1
• Do not use polypharmacy as first-line—exhaust monotherapy options including clozapine before considering combination therapy. 1